The potential Food and Drug Administration (FDA) acceptance of Anavex Life Sciences’ AVATAR as a pivotal Phase III trial would have an important bearing on the Rett syndrome market, as it could enable blarcamesine to launch at a similar time as Neuren Pharmaceuticals’ trofenitide, which is a major future competitor, says GlobalData, a leading data and analytics company.

Anavex Life Sciences’ recently announced positive results from the Phase III AVATAR (NCT03941444) trial of its innovative drug blarcamesine for the treatment of adult females with Rett syndrome. Currently, there is no cure for Rett syndrome, and no FDA approved drugs specifically for the indication. Treatment is focused on improving specific symptoms of the syndrome, such as anticonvulsants to manage seizures.

Philippa Salter, Neurology Analyst at GlobalData, comments: “There is a huge unmet need in the Rett syndrome patient population and thus signifcant opportunity for drug developers. If the FDA accepts AVATAR as a pivotal trial, blarcamesine will likely be able to launch in lock-step with trofinetide, with the two drugs sharing the first-to-market advantage. However, if the FDA requests an additional Phase III trial for blarcamesine, this would certainly provide a competitive edge to Neuren Pharmaceuticals.”

Despite the positive reported results of the AVATAR trial, questions remain whether this Phase III trial will be sufficient for a new drug application (NDA) submission to the FDA, due to questions regarding the late announcement of a change in trial phase and endpoints.

Salter continues: “The Phase III trial was originally planned as a Phase II trial and was changed midway to Phase III following positive results from an earlier Phase II trial. Additionally, the endpoint of the trial was altered from ‘change from baseline’ in Rett Syndrome Behaviour Questionnaire (RSBQ) to ‘area under the curve responder analysis’ of RSBQ, which has led to questions regarding the new endpoint and its ability to demonstrate the size of the clinical effect of blarcamesine.”

In December 2021, Neuren Pharmaceuticals announced positive results from its Phase III trial for trofenitide, which did utilize change from baseline in RSBQ as the primary endpoint. This has cast some doubt over the endpoint change for blarcamesine, making it harder to evaluate its efficacy compared to that of trofinetide.

Salter adds: “Neuren Pharmaceuticals has announced plans to submit an NDA to the FDA in mid-2022, giving trofinetide the potential to become the first approved product for Rett syndrome, before blarcamesine. Anavex is currently in discussion with the FDA over the next steps for blarcamesine’s development. Once each company’s NDA is ready, the drugs will likely see an accelerated approval based on the fast-track designation, orphan drug designation, and rare pediatric disease designation granted by the FDA for Rett syndrome.”